The compounds of formula I are described as 8-aza-9-oxo-11-thia-, -11-oxothia- and -11-dioxothia-prostanoids because of their structural relationship to the naturally-occurring prostaglandins.
The prostaglandins constitute a biologicallyprominent class of naturally-occurring, highly-functionalized C.sub.20 fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids; namely, 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetraenoic acid, and 5,8,11,14,17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, termed "prostanoic acid;" the latter is a C.sub.20 fatty acid covalently bridged between carbons 8 and 12 such as to form a trans, vicinally-substituted cyclopentane in which the carboxy-bearing side chain is "alpha" or below the plane of the ring, and the other side chain is "beta" or above the plane of the ring as depicted in the formula below. ##STR4##
The six known primary prostaglandins, PGE.sub.1, PGE.sub.2, PGE.sub.3, PGF.sub.1a, PGF.sub.2a, and PGF.sub.3a, resulting directly from anabolism of the above-cited essential fatty acids via the action of prostaglandin synthetase, as well as the three prostaglandins resulting from in vivo dehydration of the PGE's, i.e., PGA.sub.1, PGA.sub.2, and PGA.sub.3, are divided into three groups; namely, the PGE, PGF, and PGA series on the basis of three distinct cyclopentane nuclear substitution patterns as illustrated below:
______________________________________ ##STR5##
______________________________________ PG R.sub.a R.sub.b ______________________________________ E.sub.1, F.sub.1, A.sub.1 ##STR6## ##STR7## E.sub.2, F.sub.2, A.sub.2 ##STR8## ##STR9## E.sub.3, F.sub.3, A.sub.3 ##STR10## ##STR11## E.sub.0, F.sub.0, A.sub.0 ##STR12## ##STR13## ______________________________________
it should be noted that the arabic subscripts designate the number of carbon-carbon double bonds in the designated compound and that the Greek subscript used in the PGF series designates the stereochemistry of the C-9 hydroxyl group.
Further details concerning the prostaglandins can be found in recent reviews of their chemistry [J. E. Pike, Fortschr. Chem. Org. Naturst., 28, 313 (1970) and G. F. Bundy, A. Rep. in Med. Chem., 7, 157 (1972)]; biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)]; pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)]; physiological significance [E. W. Horton, Physiol. Rev., 49, 122 (1969)]; and general clinical application [J. W. Hinman, Postgrad. Med. J., 46, 562 (1970)].
The naturally-occurring prostaglandins are known to have a broad spectrum of biological activity, but at the same time are unstable metabolically. More recently, analogs of the natural prostaglandins, such as 7-[3.alpha.(3-hydroxy-3-hydrocarbylpropyl)-4-hydroxy-tetrahydro-2.beta.-th ienyl(or 2.beta.-furyl)]heptanoic acid described in U.S. Pat. No. 3,881,017 issued Apr. 29, 1975, and U.S. Pat. No. 3,883,659 issued May 13, 1975 of Isidoros Vlattas, have been reported to have prostaglandin-like activity and also to have greater stability than the natural prostaglandins. Also, Belgian Pat. No. 828,994 discloses 4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazoles which are said to have activity analogous to prostaglandins and to inhibit prostaglandin-destroying enzymes.
The compounds of our invention represented by formula I hereinabove were synthesized with the goal of providing therapeutic agents with unique activity which is specific in its therapeutic action but with enhanced metabolic stability, thus providing a useful medicament which is active when administered orally as well as parenterally. This goal has been accomplished by the synthesis of the compounds of the present invention which are effective therapeutic agents for the treatment of certain human and animal diseases, including the control of blood clots, for the promotion of renal vasodilation, and as regulators of the immune response.
The compounds of the present invention are useful as pharmaceutically-active compounds. Thus, these compounds are orally active in the treatment of conditions which are responsive to the actions of the natural prostaglandins. It is, of course, necessary to determine by routine laboratory testing which of the compounds of the present invention are most suitable for a specific end use and the recommended daily dosage.
In addition, the compounds of this invention appear to be broadly applicable in therapy as regulators of the immune response. The basis for their activity in this area is their ability to stimualte cyclic-AMP formation in cells. Agents, including the E prostaglandins, that increase cellular cyclic-AMP concentration interfere with the cell-mediated immune response by inhibiting lymphocyte expression in response to antigen, by inhibiting release of pathological mediators from sensitized lymphocytes, and by inhibiting the killing of target cells by such lymphocytes. Various assays which depend upon the measurement of some function of the immunologically competent lymphocyte can be used to demonstrate that the prostaglandin analogs of this invention are similarly active. For example, the release of lymphokines (proteins that are agents of inflammation and tissue destruction) from sensitized lymphocytes in culture is strongly inhibited by these analogs in low concentrations. Examples of the compounds of this invention which are particularly active in these assays include:
a. 7-[2-(3-Hydroxyoctyl)-4-oxo-3-thiazolidinyl]) heptanoic acid PA0 b. 7-[2-(3-Hydroxyoctyl)-1,1,4-trioxo-3-thiazolidinyl]-heptanoic acid PA0 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid PA0 7-[2-(3-hydroxyoctyl)-1,4-dioxo-3-thiazolidinyl]heptanoic acid PA0 7-[2-(3-hydroxyoctyl)-1,1,4-trioxo-3-thiazolidinyl]heptanoic acid PA0 7-{2-[4-(4-fluorophenoxy)-3-hydroxybutyl]-1,1,4-trioxo-3- thiazolidinyl}heptanoic acid PA0 7-{2-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-3-thiazolidinyl}-heptanoic acid PA0 7-[2-(3-hydroxy-1-trans-octenyl)-4-oxo-3-thiazolidinyl]-heptanoic acid PA0 7-[2-(3-hydroxy-1-trans-octenyl)-1,4-dioxo-3-thiazolidinyl]-heptanoic acid PA0 7-[2-(3-hydroxy-1-trans-octenyl)-1,1,4-trioxo-3-thiazolidinyl]heptanoic acid PA0 7-[2-(3-hydroxyoctyl)-4oxo-3-thiazolidinyl]heptanoic acid
Thus, it is apparent that the compounds of this invention are applicable to the treatment of those autoimmune diseases in whose pathogenesis a cell-mediated immune reaction is involved. Such diseases range from contact dermatitis to such chronic destructive diseases as rheumatoid arthritis and possibly multiple sclerosis and systemic lupus erythematosus.
The present prostaglandin analogs are also effective in preventing the rejection of transplanted organs. The biochemical basis for this action is the same as outlined in the preceeding paragraph, for the rejection of organ grafts is considered to be predominantly a cell-mediated immune phenomenon and the hallmark of organ rejection is the infiltration of cytotoxic lymphocytes into the graft. Direct evidence that the compounds of this invention can retard or prevent transplant rejection has been obtained in the rat renal allograft model; in this system, administration of the present analogs prevents the rejection of the transplanted kidney and the subsequent death of the host rat, which events invariably occur in the cases of untreated rats or those treated with the immunosuppressants.
In addition, certain of the compounds of this invention are particularly effective in inhibiting the aggregation in platelets in blood stimulated with collagen to cause platelet aggregation; and this, in inhibiting platelet aggregation, they are useful in preventing thrombus formation. An example is 7-[2-(3-Hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid.
Likewise, certain of the compounds of this invention are particularly effective in causing renal vasodilation in an in vivo assay in dogs. A particularly active compound in this assay is 7-[2-(3-Hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid.
Because of their biological activity and ready accessibility, the compounds of the invention are also useful in that they permit large scale animal testing, useful and necessary to understanding of these various disease conditions such as rejection of organ grafts, stroke (thrombus formation), impaired renal circulation, and the like. It well be appreciated that not all of the compounds of this invention have these biological activities to the same degree, but the choice of any particular ones for any given purpose will depend upon several factors including the disese state to be treated.
The compounds of this invention can be administered either topically or systemically (i.e., intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action).
The pharmaceutical compositions can be sterile, injectable suspensions or solutions, or solid, orallyadminsitrable, pharmaceutically-acceptable tablets or capsules; the compositions can also be intended for sublingual administration, or for suppository use.
Illustratively, a sterile injectable composition can be in the form of aqeuous or oleagenous suspensions or solutions.
The sterile, injectable composition can be an aqueous or oleagenous suspension or solution. Suspensions can be formulated according to the known art using suitable dispersing and wetting agents and suspending agents. Solutions are similarly prepared from the salt form of the compound.
Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses. Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like.
It is preferred to prepare the compositions, whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations require needless quantities of liquid. Higher concentrations than 50 mg./ml. are difficult to maintain and are preferably avoided.
Oral administration forms of the drug can also be prepared for laboratory animals or human patients provided that they are encapsulated for delivery in the gut. For either oral or parenteral use, the amount of drug to be administered is in the range of about 0.1 to 20 mg./kg. of body weight administered one to four times per day, the exact dose depending on the age, weight, and condition of the patient, and the frequency and route of administration.
The low cost and ready accessibility of the compounds of this invention make them particularly promising for applications in veterinary medicine in which field their utilities are comparable to those in human medicine.